بسم الله الرحــــــمـن الرحيم. Propionyl-L-carnitine Prevents The Progression of Cisplatin-Induced Cardiomyopathy in a Carnitine-Depleted Rat Model Mohamed.

الرحــــــ الله الرحيم مبسم ـن

Propionyl-L-carnitine Prevents The Progression of Propionyl-L-carnitine Prevents The Progression of

Cisplatin-Induced Cardiomyopathy in Cisplatin-Induced Cardiomyopathy in

a Carnitine-Depleted Rat Modela Carnitine-Depleted Rat Model

Mohamed M. Sayed-Ahmed

Abdulhakeem A. Al-Majed

Abdulaziz A. Al-Yahya

Abdulaziz M. Aleisa

Salem Al-Regay

Othman A. Al-Shabanah

Pharmacological Research

2006; 53: 278-286

FREQUENTLY ASKED FREQUENTLY ASKED QUESTIONSQUESTIONS

* What is Carnitine ?

* What are the Carnitine sources ?

* What are the physiological roles of

Carnitine ?

* What are the clinical indications of Carnitine ?

* Is Carnitine Deficiency a disease ?

* What is Carnitine Insufficiency ?

L-CARNITINE: Historical BackgroundL-CARNITINE: Historical Background

1905 Discovery

1927 Chemical structure identification

1935 Transmitter1940 Vitamin BT

1955 Cofactor in the Oxidation of long chain fatty acids

1960 Biosynthesis from Lysine

1973 Carnitine Deficiency Syndrome

Carnis

1976 Juliano and Ling, have detected a glycoprotein

and termed this protein p(ermeability)-

glycoprotein.

1981 Tsuruo et al., used Verapamil as MDR blocker.

1984 The first results of clinical trial with MDR-

reversal agents have been reported by Rogan et al.

Continue

FDA Approved Clinical FDA Approved Clinical Indications of L-CarnitineIndications of L-Carnitine

* Cardiovascular disorders

* Patients undergoing Hemodialysis

* Beta Thalassemia Major

* Male infertility

* Doxorubicin-induced cardiomyopathy

* Carnitine Deficiency Syndromes

CARNITINE DEFICIENCY

Primary Carnitine Deficiency Secondary Carnitine Deficiency

Systemic Myopathic

Acquired Medical Conditions Genetic Metabolic Error Iatrogenic Factors

-Chronic Renal and Hepatic Failure- Extreme Prematurity

-Chronic Valproate Therapy-Chronic Hemodialysis-Zidovudine Therapy

- LCAD- MCAD- SCAD

Plasma Carnitine LevelPlasma Carnitine Level

* Normal values: (40-50 umol/L)Free Carnitine (FC) 80 %Acyl-Carnitine (AC) 20 %AC/FC 0.25

* Carnitine Deficiency:Plasma Carnitine < 20 umol/L

• Carnitine Insufficiency :Normal plasma CarnitineAC/FC > 0.4

Propionyl-L-carnitine

L-carnitine

Succinyl-CoA

CAT

Propionyl-CoA

Fatty Acid Oxidation

Acetyl-CoA Krebs Cycle

ATP

PCC

CISPLATINCISPLATIN

NH3

NH3

Pt

Cl

Cl

Cisdiaminedichloroplatinum II, CDDP

CDDP-INDUCED ORGAN TOXICITYCDDP-INDUCED ORGAN TOXICITY

*

* Neurotoxicity

* Cardiomyopathy

Nephrotoxicity

CDDP CARDIOMYOPATHYCDDP CARDIOMYOPATHY

1- Electrocardiographic changes

2- Myocarditis

3- Arrythmia

4- Congestive heart failure

5- Bradycardia

6- Lethal cardiomyopathy when CDDP

is given in combination chemotherapy protocols containing MTX, 5-FU, BLM, and DOX

CDDP and L-CARNITINE

CDDP-inducedOrgan Toxicity

Increasing Carnitine Excretion

Accumulation of Platinum in Tissues

OxidativeStress

CARNITINEDEFICIENCY

CDDP-Induced Secondary CDDP-Induced Secondary Carnitine DeficiencyCarnitine Deficiency

Heuberger et al. Eur J Clin Pharmacol, 1998

CDDP inhibits Carnitine reabsorption at the proximal tubular level

CDDP increases urinary excretion of Carnitine

Sayed-Ahmed et al. Chemotherapy, 2004

Progression of CDDP-induced nephrotoxicity in carnitine depleted rats.

CDDP inhibits endogenous synthesis of L-carnitine

AIM OF WORK

* To determine whether Carnitine Deficiency is risk

factor and should be viewed as a mechanism in

CDDP-induced cardiomyopathy

* To study whether Carnitine supplementation, using

PLC, could offer protection against this toxicity, and

if so, what are the possible protective mechanisms

EXPERIMENTAL DESIGN

ControlNormal saline, I.P, 10 days

Saline-CDDP-saline 7 mg/kg, I.P.

PLC500 mg/kg, I.P., 10 days

D-carnitine500 mg/kg, I.P., 10 days

PLC-CDDP-PLC 7 mg/kg, I.P.

D-carnitine-CDDP-D-carnitine

7 mg/kg, I.P.

Carnitine-Depleted Rat Model

CAT

L-carnitine

OCTN2

Acetyl-CoA

D-carnitine

Acetyl-L-carnitine

Cell Membrane

-ve

OUT

IN

-ve

L-carnitine

Control

CDDPPLC

D-car

nitine

CDDP+D-c

arniti

ne

CDDP+PLC

0

200

400

600

*

* #

##

#

A

LD

H (

U/L

)

Control

CDDPPLC

D-car

nitine

CDDP+D-c

arniti

ne

CDDP+PLC

0

500

1000

1500

*

* #

## #

B

CK

-MB

(U

/L)

LDH

CK-MB

Control

CDDPPLC

D-car

nitine

CDDP+D-car

nitine

CDDP+PLC

0

250

500

*

* # * #

# #

A

TB

AR

S(n

mo

l/g w

et

tis

su

e)

Control

CDDPPLC

D-car

nitine

CDDP+D-car

nitine

CDDP+PLC

0.0

0.5

1.0

1.5

*

* #* #

#* #

B

GS

H(u

mo

l/g w

et

tis

su

e)

Control

CDDPPLC

D-car

nitine

CDDP+D-car

nitine

CDDP+PLC

0

1

2

3

*

* #

* #

# #

C

NO

( x)

(um

ol/g

we

t ti

ss

ue

)

Oxidative Stress Biomarkers

TBARS,

GSH,

NO(x)

Control

CDDPPLC

D-car

nitine

CDDP+D-c

arniti

ne

CDDP+PLC

0

50

100A

To

tal c

arn

itin

eS

eru

m (

um

ol/l

)

Control

CDDPPLC

D-car

nitine

CDDP+D-car

nitine

CDDP+PLC

0

1000

2000

*

*

** #

#

#B

To

tal c

arn

itin

eH

eart

(u

mo

l/g w

et

tis

su

e)

Total Carnitine

Serum

Heart

Control

CDDPPLC

D-car

nitine

CDDP+D-car

nitine

CDDP+PLC

0

250

500

750

1000

1250

*

** #

#

#

AT

P(n

mo

l/g

wet

tis

sue)

ADENOSINE TRIPHOSPHATE

HISTOPATHOLOGY

CONCLUSION

 * Carnitine Deficiency is a risk factor and should be

viewed as a mechanism during development of

CDDP-induced cardiomyopathy

* Oxidative stress plays an important role in CDDP-

induced cardiomyopathy

* Carnitine supplementation, using PLC, prevents the progression of CDDP-induced

cardiomyopathy

* It would be worthwhile studying the effects of carnitine supplementation in CDDP- treated cancer patients, in the hope of reducing CDDP-induced nephrotoxicity, ototoxicity, and cardiomyopathy

CONCLUSION

AcknowledgementsAcknowledgements

The present study was supported by Operating Grant from Research Center, College of Pharmacy, King Saud University.

CPRC 154

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